TY - JOUR
T1 - MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming
AU - Mohammed Ismail, Wazim
AU - Mazzone, Amelia
AU - Ghiraldini, Flavia G.
AU - Kaur, Jagneet
AU - Bains, Manvir
AU - Munankarmy, Amik
AU - Bagwell, Monique S.
AU - Safgren, Stephanie L.
AU - Moore-Weiss, John
AU - Buciuc, Marina
AU - Shimp, Lynzie
AU - Leach, Kelsey A.
AU - Duarte, Luis F.
AU - Nagi, Chandandeep S.
AU - Carcamo, Saul
AU - Chung, Chi Yeh
AU - Hasson, Dan
AU - Dadgar, Neda
AU - Zhong, Jian
AU - Lee, Jeong Heon
AU - Couch, Fergus J.
AU - Revzin, Alexander
AU - Ordog, Tamas
AU - Bernstein, Emily
AU - Gaspar-Maia, Alexandre
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macro-Bound Enhancers’, that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.
AB - Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macro-Bound Enhancers’, that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.
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U2 - 10.1038/s42003-023-04571-1
DO - 10.1038/s42003-023-04571-1
M3 - Article
C2 - 36823213
AN - SCOPUS:85148806199
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 215
ER -